The nociceptin receptor antagonist [Nphe1,Arg14,Lys15]nociceptin/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin/orphanin FQ on the HPA axis in rats

Endogenous Nociceptin System Involvement in Stress Responses and Anxiety Behavior

“…These two physiological systems can be considered as major effector pathways for maintenance of homeostasis during stress. On the basis of the preproN/OFQ knockout phenotype, N/OFQ was proposed as an endogenous antistress peptide opposing the stress-promoting effects of the HPA axis (Koster et al, 1999), however, we and others have provided evidence indicating that central N/OFQ in fact activates the HPA axis in rats (Devine, Watson, & Akil, 2001;Leggett, Harbuz, Jessop, & Fulford, 2006;Leggett, Jessop, & Fulford, 2007). i.c.v.…”

“…Although CRH mRNA expression was stimulated by i.c.v. N/OFQ injection, no changes in arginine vasopressin mRNA were seen (Leggett et al, 2006). The evidence for N/OFQ and CRH interactions is significant given the role of CRH in the integration of neurobehavioral responses to stress and anxiety.…”

“…As prolonged stress can predispose to physical or mental disorders including inflammatory diseases, anxiety, and depression (Sternberg, Chrousos, Wilder, & Gold, 1992), N/OFQergic mechanisms that contribute significantly to stress adaptation have attracted attention. Central N/OFQ peptide infusion activates the HPA axis acutely via binding to NOP receptors, as we have shown that coadministration with the selective peptidic antagonist, UFP-101, can fully attenuate the N/OFQ-induced stimulatory effect on the HPA axis in rats (Leggett et al, 2006). Our studies employing the UFP-101 antagonist revealed an interesting role of endogenous N/OFQ function in the regulation of HPA axis activity depending on the type of stressor and time of day of experiment.…”

“…We confirmed these findings in our own laboratory and also examined the mechanisms whereby N/OFQ activates the stress axis. We have shown that central N/OFQ injection stimulates corticotrophin-releasing hormone (CRH) neurones of the parvocellular paraventricular nucleus (PVN) and synthesis of the ACTH precursor, pro-opiomelanocortin (POMC), in pituitary corticotrophs (Leggett et al, 2006). The increased hypothalamic CRH and pituitary POMC mRNAs are associated with elevated plasma corticosterone levels at 30 min postinjection.…”

“…Identification of novel candidates involved in fear regulation will benefit understanding of the basis of mental disorders associated with intense fear such as post-traumatic stress and anxiety disorders, in addition to other disorders associated with aberrant behavior like schizophrenia and drug addiction (Sato, 1992;Sinha, Catapano, & O'Malley, 1999). Recent research into the role of N/OFQ in the amygdala (Roozendaal, Lengvilas, McGaugh, Civelli, & Reinscheid, 2007;Uchiyama, Toda, Hiranita, Watanabe, & Eyanagi, 2008), in memory (Higgins et al, 2002), anxiety (Fernandez et al, 2004;Green, Barbieri, Brown, Chen, & Devine, 2008;Jenck et al, 2000;Uchiyama et al, 2008;Varty et al, 2005;Vitale, Arletti, Ruggieri, Cifani, & Massi, 2006), and stress (Dawe et al, 2010;Delaney et al, 2012;Devine et al, 2001;Leggett et al, 2006Leggett et al, , 2007Leggett et al, , 2009Rodi et al, 2008) demonstrates the clear potential of this peptidergic system with regard to emotional functions. The emerging data is compelling, demanding further investigation of N/OFQ's contribution to the basic fear network and fear learning.…”